Structure-Based Design of Peptide Entry Inhibitors against Ebola Virus Infection

基于结构的抗埃博拉病毒感染肽进入抑制剂的设计

• 批准号: 10322758
• 负责人: Shi-hua Xiang
• 金额: $ 20.91万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322758
• 关键词: Affect; Affinity; Africa; Binding; Binding Sites; Biological Assay; Biomedical Research; Blood; Cells; Cessation of life; Clinical Trials; Communicable Diseases; Containment; Crystallization; Cytoplasm; Dangerousness; Disease Outbreaks; Ebola; Ebola virus; Endosomes; Evaluation; Family; Filovirus; Glycoproteins; Human; Inbred BALB C Mice; Infection; Liquid substance; Marburgvirus; Measures; Membrane Fusion; Methods; Monoclonal Antibodies; Mus; Organ; Outcome; Peptides; Persons; Pharmaceutical Preparations; Pharmacy facility; Research Institute; Statistical Data Interpretation; Structure; Surface Plasmon Resonance; Testing; Texas; Therapeutic; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Zaire Ebola virus; base; college; design; drug development; efficacy testing; fight against; in vivo Model; in vivo evaluation; inhibitor; mortality; mouse model; neutralizing antibody; nonhuman primate; peptide drug; prevent; receptor; receptor binding; vaccine access; viral entry inhibitor

Abstract Ebola viruses (EBOV) along with Marburg viruses (MARV) belong to the Filoviridae family which infects humans and nonhuman primates and causes outbreaks with a high mortality up to 90%. We do not have approved drugs for treating this deadly viral disease and therefore it is urgent to develop therapeutics to cope with the dangerous outbreaks. In this project, we propose to develop peptide based inhibitors targeting the receptor binding site (RBS) to block viral infection. We will conduct structure based design using the available co-crystal structures of the NPC1 receptor or monoclonal antibodies bound to the viral glycoprotein. The initial evaluation will utilize pseudo- typed viruses to test viral entry in a cell based assay. The best peptide candidates from these assays will subsequently be tested in a BSL-4 containment facility using replication competent viruses for entry inhibition tests. In vivo evaluations of qualified candidates will be conducted in a virus challenge mouse model to measure protection efficacy. After all these evaluations, promising candidates could be advanced to nonhuman primates or human clinical trials.

摘要 埃博拉病毒(EBOV)与马尔堡病毒(Marv)同属丝状病毒科 感染人类和非人类灵长类动物，并导致高达90%的死亡率。 我们还没有批准的药物来治疗这种致命的病毒性疾病，因此迫切需要 开发治疗方法来应对危险的疫情。在这个项目中，我们建议开发 以受体结合位点(RBS)为靶点的多肽抑制剂，可阻断病毒感染。我们会 利用NPC1受体的可用共晶结构进行基于结构的设计 与病毒糖蛋白结合的单抗。初始评估将利用伪 在基于细胞的化验中测试病毒的类型。这些中最好的候选多肽 随后将在BSL-4安全壳设施中使用复制能力进行测试 病毒进入抑制试验。对合格候选人的活体评估将在 用病毒攻击小鼠模型来衡量保护效果。在所有这些评估之后， 有希望的候选者可能会进入非人类灵长类动物或人类临床试验。